Varicose veins are focal vessel dilitations present in up to 30% of the adult population and clearly associated with significant morbidity. Despite the prevalence and marked health care costs associated with this syndrome, there has been a paucity of scientific studies aimed at defining the mechanism(s) responsible for varicosities and chronic venous insufficiency . In preliminary data, progression of venous disease was associated with a marked decrease in over twenty lipoprotein related genes normally associated with adipocyte dedifferentiation. There was also an increase in genes known to be involved in ubiquitin-dependent protein degradation in skeletal muscle. Therefore, the central hypothesis of this proposal is that degeneration and disorganization of smooth muscle cells in veins compromises the vessel wall structural integrity through (1) changes in lipoprotein metabolism that influence smooth muscle cell proliferation and (2) regulated protein degradation, causing smooth muscle proteolysis and remodeling. We propose to: 1) Characterize the changes seen in early venous disease, specifically, alterations in lipid metabolism related proteins, and determine their contribution to smooth muscle cell integrity; 2) Study the mechanisms that contribute to proteolysis-dependent smooth muscle cell changes and loss of structural integrity in varicose veins; and 3) Examine the relevance of lipoprotein metabolism and the ubiquitin-proteasome pathway in a long-term model of venous hypertension. In summary, this proposal wil l use a combination of molecular, histological, and in vivo studies to define the mechanism(s) that contribute to the development of varicose vein s and chronic venous insufficiency as well as establish models needed for the study of potential therapies. Although the development of venous disease is multifactorial, the pivotal processes responsible for triggering early disease as well as progression to chronic disease are unknown. This application will study an extremely common vascular disease that is not currently under investigation by any NIH-funded programs and will allow the applicant to utilize their fundamental interest in vascular biology, surgical research skills, and their clinical interest in the treatment of varicose veins. [unreadable] [unreadable]